Significant new advances in 2006-2007 are highlighted below. <b>TRalpha1PV causes impaired adipogenesis</b> <i>TRalpha1<sup>PV/+</sup></i> mice exhibit dwarfism with severe reduction in weight gain. We carried out studies to identify the defects contributing to severe weight reduction of <i>TRalpha1<sup>PV/+</sup></i> mice. We found that white adipose mass, but not of brown adipose tissue, is markedly reduced in <i>TRalpha1<sup>PV/+</sup></i> mice. The expression of peroxisome proliferator-activated receptor gamma (PPARgamma), the key regulator of adipogenesis, is repressed at both the mRNA and protein levels in white adipose tissue of <i>TRalpha1<sup>PV/+</sup></i> mice. Moreover, TRalpha1PV also acts to inhibit the transcription activity of PPARgamma by competition with PPARgamma for binding to PPARE and for heterodimerization with RXR. Thus, mutations of the TRalpha1 severely affect adipogenesis via cross talk with the PPARgamma-signaling by repression of critical genes in adipogenesis, contributing to the phenotypic expression of severely reduced body weight observed in dwarfism. <b>The pituitary tumor-transforming gene (PTTG) promotes thyroid tumor progression by increasing cell proliferation and metastatic spread in a mouse model of thyroid cancer</b> The over-expressed PTTG in thyroid tumors of <i>TRbeta<sup>PV/PV</sup></i> mice, similar to human thyroid cancer, prompted us to elucidate how PTTG promotes thyroid carcinogenesis by studying the offspring of <i>TRbetaPV</i> mice crossing with mice lacking PTTG (<i>PTTG<sup>-/-</sup></i> mice). The thyroids of <i>TRbeta<sup>PV/PV</sup>PTTG<sup>-/-</sup></i> mice are significantly smaller than those of <i>TRbeta<sup>PV/PV</sup></i> mice. The decreased thyroid proliferation is mediated by a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Furthermore, <i>TRbeta<sup>PV/PV</sup>PTTG<sup>-/-</sup></i> mice have a significant decrease in vessel density, vascular invasion, and less development of lung metastasis as they progressively age. Our results highlight the dual roles of PTTG as a regulator of thyroid growth and contributor to tumor progression. <b>TRbetaPV activates the PI3K signaling via protein-protein interaction</b> Given that AKT/protein kinase B is activated during thyroid carcinogenesis, we further sought to understand the molecular mechanisms underlying the activation of AKT signaling during thyroid carcinogenesis in <i>TRbeta<sup>PV/PV</sup></i> mice. We found that in thyroid tumors, the TRbetaPV mutant binds significantly more to the PI3K-regulatory subunit p85alpha, resulting in a greater increase in kinase activity than that seen with TRbeta in wild type mice. The association of p85alpha with TRbeta or TRbetaPV occurs in both the cytoplasmic and nuclear compartment. The TRbetaPV-induced activation of the PI3K-AKT-mammalian target of the rapamycin (mTOR)-p70<sup>S6K</sup> pathway was observed in both the cytoplasmic and nuclear compartment, whereas the activation of the PI3K-integrin-linked kinase-matrix metalloproteinase-2 pathway was detected mainly in the extranuclear compartment. These results suggest that TRbetaPV, via the activation of p85alpha, could act to affect PI3K downstream signaling in both the nuclear and extranuclear compartment, thereby contributing to thyroid carcinogenesis. Importantly, we uncovered a novel mechanism by which a mutant TR acts to activate the PI3K activity via protein-protein interactions. Taken together, our studies show that PI3K would be an excellent target for thyroid cancer therapy as there are specific small molecule inhibitors available for testing. <b>The steroid receptor coactivator-3 (SRC-3) is a tumor promoter of follicular thyroid carcinogenesis</b> SRC-3 is a tumor promoter in many human cancers. However, its role in thyroid tumor progression previously was not clear. We therefore assessed the roles of SRC-3 in thyroid carcinogenesis <i>in vivo</i> by using the offspring from the crossing of TRbeta<sup>PV/PV</sup> and <i>SRC-3<sup>-/-</sup></i> mice. <i>TRbeta<sup>PV/PV</sup></i> mice deficient in SRC-3 (<i>TRbeta<sup>PV/PV</sup>SRC-3<sup>-/-</sup></i> mice) have significantly increased survival, decreased thyroid tumor growth, delayed tumor progression, and lower incidence of distant metastasis as compared with TRbeta<sup>PV/PV</sup> mice with SRC-3 (<i>TRbeta<sup>PV/PV</sup>SRC-3<sup>+/+</sup></i> mice). Further <i>in vivo</i> and <i>in vitro</i> analysis of multiple signaling pathways indicated that SRC-3 deficiency could lead to (a) inhibition of cell cycle progression at the G1/S transition via controlling the expression of cell cycle regulators, such as E2F1; (b) induction of apoptosis by controlling the expression of the Bcl-2 and caspase-3 gene; (c) suppression of neovascularization and metastasis, at least in part, through modulating the vascular endothelial growth factor gene expression. Thus, the present study shows that SRC-3 is a novel tumor promoter in thyroid carcinogenesis via regulating multiple target genes and signaling pathways and raises the possibility that it could be a potential molecular target